Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.